In vitro somatostatin is a potent inhibitor of intestinal ion secretion in animal models and cultured human cell lines, providing a rationale for its use in secretory diarrheas. However, the effects of somatostatin on ion transport in native human colonic epithelium have not been reported. In this study the effects of somatostatin and octreotide on the basal short-circuit current and the cAMP- and Ca2+-stimulated short-circuit current were studied in isolated human colonic mucosa mounted in Ussing chambers. Under basal conditions somatostatin and octreotide (1 micromol/liter) stimulated a small, bumetanide-sensitive increase in short-circuit current. Following stimulation of secretion with prostaglandin E2, somatostatin and octreotide further increased the short-circuit current in a dose dependent fashion (ED50 approximately 10 nmol/liter for both). This stimulation of short-circuit current was not affected by pretreatment of the tissue with basolateral tetrodotoxin (1 micromol/liter) or mucosal amiloride (10 micromol/liter). In contrast, somatostatin and octreotide had no effect when secretion was stimulated with 8-bromo-cAMP, and pretreatment of the tissue with somatostatin and octreotide (0.1 micromol/liter) did not alter the secretory response to carbachol. The absence of any inhibitory effect of somatostatin and octreotide on electrogenic secretion in the human colon may explain the variable results obtained when somatostatin or octreotide are used for the treatment of secretory diarrheas.